Pharmacology Update

Valdecoxib Tablets (Bextra—Pharmacia)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

A third cox-2 inhibitor has been approved by the FDA for marketing. Valdecoxib is a selective cyclooxygenase-2 inhibitor similar to celecoxib (CelebrexTM) and rofecoxib (Vioxx®). The drug will be marketed by Pharmacia and Pfizer as "Bextra."

Indications

Valdecoxib is indicated for the relief of the signs and symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA) in adults. It is also indicated for the treatment of primary dysmenorrhea.1

Dosage

The recommended dose of valdecoxib is 10 mg once daily for both OA and RA. For primary dysmenorrhea, the recommended dose is 20 mg twice daily as needed.1

Valdecoxib can be taken without regard to meals, however, food can delay the rate of absorption and delay peak concentration by 1-2 hours.1 Valdecoxib should not be used in patients with aspirin-sensitive asthma and should be used with caution in patients with pre-existing asthma.1

Potential Advantages

Valdecoxib appears to offer the same potential advantage as other COX-2 inhibitors, a lower risk of gastrointestinal side effects. A lower risk of endoscopically determined gastroduodenal ulcers compared to naproxen (500 mg twice daily) has been reported in a 12-week study (n = 466) in patients with OA.2 The incidences of ulcers were 4% for placebo, 10% for naproxen, and 3%, 3%, and 5% for valdecoxib 5 mg, 10 mg, and 20 mg daily, respectively. The incidence of ulceration was statistically significant for both the 5 mg and 10 mg doses compared to naproxen at P < 0.05 and P < 0.01, respectively, however the rate of ulceration for the 20 mg dose was not statistically different. In a larger study (n = 1217), higher doses of valdecoxib (20 mg or 40 mg twice daily) had lower incidences of endoscopically determined ulcers at 14 weeks than naproxen 500 mg twice daily in patients with OA or RA.3 The incidences ranged 3-5% for 40 mg daily, 6-9% for 80 mg, vs. 16-20% for naproxen. Both doses of valdecoxib were statistically lower than naproxen.

Potential Disadvantages

Concomitant administration of valdecoxib and warfarin resulted in mean increase (12-15%) in plasma levels of warfarin, mean INR values as well as intrasubject variability.1 Monitoring of these patients is recommended during the first few weeks after initiation of valdecoxib therapy.

Valdecoxib decreases the clearance of lithium and patients should be monitored if coadministration is appropriate. Valdecoxib is metabolized primarily by cytochrome P450 isoenzymes 3A4 and 2C9, therefore, drug-drug interactions are possible with an inhibitor or inducer of these isoenzymes. Borderline elevations of liver enzymes (ie, ALT, AST) have been reported in about 8% of patients treated with valdecoxib. Hemoglobin or hematocrit should be assessed in patients on long-term therapy if there are signs or symptoms of anemia. Hypertension and peripheral edema have been reported in up to 2.1% and 3%, respectively.1 COX-2 inhibitors may affect the balance between prothombotic and antithrombotic eicosanoids and data have suggested that these drugs may increase the risk of cardiovascular events (eg, myocardial infarction), particularly in patients at risk for these events.4,9

Comments

Valdecoxib is a selective COX-2 inhibitor similar to celecoxib and rofecoxib. It has been studied in patients with OA, RA, and primary dysmenorrhea. Findings have been reported as abstracts or in the package insert, thus full details are not available. In patients with OA of the knee (n = 1019) or hip (n = 466), randomized, double-blind, placebo-controlled 12-week studies indicated that valdecoxib (5-10 mg daily) is better than placebo and comparable to naproxen (500 mg twice daily).2,5 Efficacy was assessed using Patient and Physician’s Global Assessment of Arthritis. Similarly in RA (n = 1089), valdecoxib (10, 20, 40 mg daily) was superior to placebo and comparable to naproxen (500 mg twice daily) as assessed by ACR20.6 ACR20 responders at 12 weeks were 32% for placebo, 44% for naproxen, and 46-49% for valdecoxib. No clear difference was detected between the various doses of valdecoxib. For patients with moderate-to-severe primary dysmenorrhea, a single dose of valdecoxib 40 mg daily was comparable to a single dose of naproxen sodium 550 mg and appeared to be superior to valdecoxib 20 mg based on assessment of pain intensity difference over 12 hours.7 As with other COX-2 inhibitors, valdecoxib has no antiplatelet activity. The risk of renal toxicity is generally considered to be similar between COX-2 inhibitors and traditional NSAIDs.9 There are no comparative studies between valdecoxib and other COX-2 inhibitors in OA or RA. A recent study suggested that a single dose of valdecoxib 40 mg provided a faster onset of analgesia and more effective pain relief than a single dose of rofecoxib 50 mg in the management of postoperative pain associated with oral dental surgery.10 The average wholesale cost for valdecoxib 10 mg for the treatment of OA is $2.92 per day compared to $2.75 for rofecoxib (12.5 mg/d) and celecoxib (200 mg/d).

Clinical Implications

Valdecoxib is another COX-2 inhibitor, joining the blockbuster drugs celecoxib and rofecoxib. It is not clear whether valdecoxib offers any significant advantage or disadvantage over its predecessors. The manufacturer is expected to promote the faster onset of valdecoxib compared to other COX-2 inhibitors and long duration of action.8 However, the clinical relevance remains to be established. Pharmacia is expected to seek approval for a pain indication. 

References

1. Bextra Product Information. Pharmacia Corporation. November 2001.

2. Kivitz A, et al. Arthritis Rheum. 2001;44(9):S134.

3. Agrawal N, et al. Arthritis Rheum. 2001;44(9):S372.

4. Mukherjee D. JAMA. 2001;286:954-959.

5. Makarowski W, et al. Arthritis Rheum. 2001;44(9): S134.

6. Bensen W, et al. Arthritis Rheum. 2001;44(9):S369.

7. Torri S, et al. Fertil Steril. 2001;76(3 suppl 1):S95.

8. FDC Report. The Pink Sheet. February 11, 2002.

9. FitzGerald G, Patrono C. N Engl J Med. 2001;345(6): 433-442.

10. Fricke J, et al. Am J Ther. 2002;9(2):89-97.

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.